IL RITUXIMAB NEL TRATTAMENTO DELLA
PORPORA TROMBOTICA TROMBOCITOPENICA




                                             Er...
THROMBOTIC MICROANGIOPATHY
Hemolytic Uremic Syndrome - Thrombotic Thrombocytopenic Purpura



                   Definitio...
THROMBOTIC THROMBOCYTOPENIC PURPURA

Incidence of TTP estimated at 4 cases per 1 million/year

TTP is more frequent among ...
• Deficiency of the von Willebrand Factor (VWF)-
  cleaving protease, ADAMTS13, has been
  reported in the majority of pat...
VWF-CLEAVING PROTEASE

Member     of    ADAMTS     family  (A    Disintegrin-like     And
Metalloprotease, with ThromboSpo...
REDUCED ADAMTS13 ACTIVITY IN HEALTH AND DISEASE

        - elderly
        - newborns
        - third trimester of pregnan...
ADAMTS13 MUTATIONS IN TTP CAUSE SEVERELY REDUCED
    PLASMA ADAMTS13 CONCENTRATION

Family A

ADAMTS13 antigen (ng/mL)    ...
ACQUIRED IDIOPATHIC TTP

Undetectable plasma levels of ADAMTS13
                                   Furlan et al., Blood, 1...
• Deficiency of the von Willebrand Factor (VWF)-
  cleaving protease, ADAMTS13, has been
  reported in the majority of pat...
OLD DAYS OF TREATMENT OF HUS/TTP

                                      Plasma manipulation
               100
           ...
• Plasma exchange is the treatment of choice for
  patients with acquired TTP

• Congenital TTP responds to plasma infusio...
DIFFERENTIAL DIAGNOSIS BETWEEN TTP ASSOCIATED WITH
 GENETIC OR IMMUNE-MEDIATED ADAMTS13 DEFICIENCY IS
      IMPORTANT TO G...
INTERNATIONAL REGISTRY OF
                                                                                           RECUR...
INTERNATIONAL REGISTRY OF
              RECURRENT AND FAMILIAL HUS/TTP


• A congenital deficiency of ADAMTS13 was found i...
RITUXIMAB, A HUMANIZED CHIMERIC ANTIBODY
DIRECTED AGAINST THE CD20 ANTIGEN IN B
CELLS, HAS BEEN PROVEN EFFECTIVE IN
INDUCI...
http://www.clinicaltrials.gov/ct2/home


•   Found 17 studies with search of: Thrombotic Thrombocytopenic Purpura


Use of...
REGISTRY ANALYSES - Aims of the evaluation

• To verify if Rituximab, in patients with anti-ADAMTS13 antibodies,
  can ind...
Patients

• Adult patients with at least one episode of TTP

• Reduced ADAMTS13 activity (<6%) and high titers of anti-
  ...
CHARACTERISTICS OF TTP PATIENTS BEFORE TREATMENT
                 WITH RITUXIMAB

Patient     Age at      Age at 1st     T...
RITUXIMAB TREATMENT IN ACUTE
                                           REFRACTORY TTP

                                  ...
PROPHYLAXIS WITH RITUXIMAB IN RECURRENT TTP

A patient with recurrent TTP due to high titers of ADAMTS13 inhibitors who
us...
PROPHYLAXIS WITH RITUXIMAB IN RECURRENT TTP

- Rituximab caused progressive disappearance of inhibitors and increase of pr...
PROPHYLAXIS WITH RITUXIMAB IN RECURRENT TTP

Patient    Treatment                                                         ...
TTP PATIENT TREATED WITH RITUXIMAB BOTH
                       IN ACUTE AND REMISSION PHASES

                            ...
CONCLUSIONS

Our observations confirmed that Rituximab as adjunctive
therapy in patients with TTP not responding to
conven...
RITUXIMAB FOR TREATMENT OF aHUS WITH ANTI-CFH ANTIBODIES

 In a 10-year-old girl with high levels of anti-CFH autoantibodi...
Laboratory           Clinical
 Marina Noris        Giuseppe Remuzzi
 Roberta Donadelli   Piero Ruggenenti
 Chiara Mossali ...
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Daina Erica Torino 13° Convegno Patologia Immune E Malattie Orfane 21 23 Gennaio 2010 [Modalità Compatib

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Daina Erica Torino 13° Convegno Patologia Immune E Malattie Orfane 21 23 Gennaio 2010 [Modalità Compatib

  1. 1. IL RITUXIMAB NEL TRATTAMENTO DELLA PORPORA TROMBOTICA TROMBOCITOPENICA Erica Daina Centro Centro di Ricerche Cliniche per le Malattie Rare Aldo e Cele Daccò Istituto Mario Negri 22 Gennaio 2010 Torino
  2. 2. THROMBOTIC MICROANGIOPATHY Hemolytic Uremic Syndrome - Thrombotic Thrombocytopenic Purpura Definition A multisystem disease with predominant renal involvement in HUS and neurological signs in TTP, characterized by a triad of symptoms: - microangiopathic hemolytic anemia - thrombocytopenia - formation of platelet-rich thrombi in the microcirculation
  3. 3. THROMBOTIC THROMBOCYTOPENIC PURPURA Incidence of TTP estimated at 4 cases per 1 million/year TTP is more frequent among women (female/male ratio 3:2) The most commom form of TTP is acquired ( “sporadic”) Relapses following an initial episode of acquired TTP are described, with about one third of cases becoming recurrent Familial TTP usually manifests in the postnatal period or during infancy, although in some cases the onset is later at 20-30 years Patients with familial TTP tipically exhibit a relapsing course
  4. 4. • Deficiency of the von Willebrand Factor (VWF)- cleaving protease, ADAMTS13, has been reported in the majority of patients with TTP
  5. 5. VWF-CLEAVING PROTEASE Member of ADAMTS family (A Disintegrin-like And Metalloprotease, with ThromboSpondin type 1 motif) Named ADAMTS 13 1427 aa residues Genomic DNA mapped to human chromosome 9q34 mRNA detected in liver Zheng et al., J Biol Chem, 2001 Gerritsen et al., Blood, 2001 Fujikawa et al., Blood, 2001 Soejima et al., J Biochem, 2001
  6. 6. REDUCED ADAMTS13 ACTIVITY IN HEALTH AND DISEASE - elderly - newborns - third trimester of pregnancy - uremia - after major surgery - inflammatory states - liver cirrhosis Mannucci et al., Blood, 2001
  7. 7. ADAMTS13 MUTATIONS IN TTP CAUSE SEVERELY REDUCED PLASMA ADAMTS13 CONCENTRATION Family A ADAMTS13 antigen (ng/mL) 77 1580 79 731 82 786 ADAMTS13 activity (%) < 6% 108% < 6% 62% < 6% 67% 5 10 1 6 5 10 6 10 5 10 5 1 Heterozygous 3 5 5 5 3 5 5 5 3 5 3 5 2 4 3 5 2 4 / 4 2 4 2 / Val88Met(metalloprotease) 7 7 7 7 7 7 8 7 7 7 7 7 7 7 5 8 7 6 5 6 8 5 8 5 7 7 Gly1239Val (CUB1) 3 7 7 / 3 7 7 3 7 3 Family B Family C ADAMTS13 antigen (ng/mL) < 62.5 < 62.5 < 62.5 ADAMTS13 activity (%) < 6% < 6% < 6% 6 6 6 6 6 6 Homozygous 5 5 Homozygous 5 1 5 1 5 1 5 1 3 3 6 6 5 5 5 5 Arg1123Cys (TSP8) 5 5 Arg1219Trp (CUB1) 6 6 6 6 4 4 6 6 6 6
  8. 8. ACQUIRED IDIOPATHIC TTP Undetectable plasma levels of ADAMTS13 Furlan et al., Blood, 1998 The activity is normal after recovery Antibodies that inhibit enzyme activity in plasma are found in 48 to 80 % of these patients Tsai et al., N Engl J Med, 1998 Veyradier et al., Blood, 2001
  9. 9. • Deficiency of the von Willebrand Factor (VWF)- cleaving protease, ADAMTS13, has been reported in the majority of patients with TTP • ADAMTS13 deficiency may be either constitutive, due to mutations in the ADAMTS13 gene, or acquired due to the presence of circulating anti-ADAMTS13 autoantibodies
  10. 10. OLD DAYS OF TREATMENT OF HUS/TTP Plasma manipulation 100 Aspirin 80 Survival (%) 60 40 20 0 1925 1964 1980 1990 Bell et al NEJM, 1991 Rock et al NEJM,1991 Goldenfarb et al, JAMA 1973
  11. 11. • Plasma exchange is the treatment of choice for patients with acquired TTP • Congenital TTP responds to plasma infusion Author: Deborrah Symonette http://emedicine.medscape.com/article/779969-overview Updated: Sep 16, 2009
  12. 12. DIFFERENTIAL DIAGNOSIS BETWEEN TTP ASSOCIATED WITH GENETIC OR IMMUNE-MEDIATED ADAMTS13 DEFICIENCY IS IMPORTANT TO GUIDE SPECIFIC TREATMENTS Genetic ADAMTS13 deficiency: - replacement with plasma of the defective activity Immuno-mediated ADAMTS13 deficiency: - plasmapheresis to remove anti-ADAMTS13 autoantibodies and to replace the metalloprotease - inhibition of the autoantibodies production through treatment with glucocorticoids, immunosuppressive agents, or rituximab
  13. 13. INTERNATIONAL REGISTRY OF RECURRENT AND FAMILIAL HUS/TTP Participating Centers 180 UK Switzerland Denmark Patients 600 Germany HUS/TTP 473/127 Familial 86/19 Trento Sporadic 387/108 Belgium VareseBergamo BresciaTreviso Monza MilanoVicenza Torino Padova Genova Pavia Parma Canada Firenze Poland Czech R. Estonia USA Roma Portugal Sassari Foggia Salerno Bari Spain Greece Iran Serbia Cagliari Reggio Calabria Palermo Israel Turkey Chile Argentina South Africa UAE Saudi Arabia http://villacamozzi.marionegri.it Malaysia Japan Australia
  14. 14. INTERNATIONAL REGISTRY OF RECURRENT AND FAMILIAL HUS/TTP • A congenital deficiency of ADAMTS13 was found in 15 patients • Undetectable ADAMTS13 activity (<6%) due to the presence of anti- ADAMTS13 inhibitors was found in 28 of 32 patients, in the acute phase, and in 14 of 53 patients, during remission • 10 patients with a severe and recurrent form of TTP showed persistence of high titers of autoantibodies in remission
  15. 15. RITUXIMAB, A HUMANIZED CHIMERIC ANTIBODY DIRECTED AGAINST THE CD20 ANTIGEN IN B CELLS, HAS BEEN PROVEN EFFECTIVE IN INDUCING REMISSION IN PATIENTS REFRACTORY TO ANY OTHER TREATMENT Chemnitz et al., Am J Hematol, 2002 Gutterman et al., Blood Cells Mol Dis, 2002 Tsai et al., Eur J Haematol, 2003 Yomtovian et al., Br J Haematol, 2004 Fakhouri et al., Ann Int Med, 2004 Sallah et al., J Thromb Haemost, 2004
  16. 16. http://www.clinicaltrials.gov/ct2/home • Found 17 studies with search of: Thrombotic Thrombocytopenic Purpura Use of Rituximab Treatment in Addition to Standard Care for Newly Presenting TTP Rituximab in Patients With Relapsed or Refractory TTP-HUS Evaluating the Effectiveness of Adding Rituximab to Standard Treatment for TTP (The STAR Study) The Use of Rituximab in Acute Thrombotic Thrombocytopenic Purpura (TTP)
  17. 17. REGISTRY ANALYSES - Aims of the evaluation • To verify if Rituximab, in patients with anti-ADAMTS13 antibodies, can induce remission of acute refractory TTP and can prevent relapses of recurrent forms • To verify if Rituximab can restore a significant ADAMTS13 plasma activity (>10%) with no detectable inhibitors • To evaluate whether the reapparance of high titer of ADAMTS13 inhibitors may be an indicator for retreatment
  18. 18. Patients • Adult patients with at least one episode of TTP • Reduced ADAMTS13 activity (<6%) and high titers of anti- ADAMTS13 antibodies at onset in patients with refractory TTP • Reduced ADAMTS13 activity (<6%) and high titers of anti- ADAMTS13 antibodies in at least two assays performed at least 3 months apart, and at the time of prophylactic treatment
  19. 19. CHARACTERISTICS OF TTP PATIENTS BEFORE TREATMENT WITH RITUXIMAB Patient Age at Age at 1st Total number Brain/Kidney Previous Sex diagnosis treatment with of TTP involvement treatments (yr) Rituximab (yr) episodes Plasma, steroids, vincristine, 01/F 23 23 1 ?/No defibrotide Plasma, steroids, vincristine, 02/F 57 57 1 Yes/Yes cyclophosphamide, cyclosporine Plasma, steroids, intravenous 03/M 48 58 >10 Yes/Yes Ig, cyclosporine, splenectomy Plasma, steroids, 04/M 37 42 3 Yes/Yes intravenous Ig Plasma, steroids, 05/F 32 49 10 No/Yes intravenous Ig, azathioprine Plasma, steroids, intravenous 06/M 27 31 5 No/Yes Ig, vincristine, vinblastine Data from the International Registry of Familial and Recurrent HUS/TTP
  20. 20. RITUXIMAB TREATMENT IN ACUTE REFRACTORY TTP FOLLOW-UP Patient Treatment no no Pre 2 mo 6 mo 10 mo 12 mo 15 mo 27 mo ADAMTS13# -activity <6 52 54 55 70 67 01 1 -inhibitors 2.2 Neg Neg Neg Neg Neg CD20% 11 1 0 1 nd nd ADAMTS13# -activity <6 62 69 <6 68 76 02 1 -inhibitors 2.3 Neg Neg Pos Neg Neg Prophylactic treatment CD20% 8 1 1 nd nd # ADAMTS13 activity is expressed as % (normal range: 50-150%) Inhibitors are expressed as Bethesda units Data from the International Registry of Familial and Recurrent HUS/TTP
  21. 21. PROPHYLAXIS WITH RITUXIMAB IN RECURRENT TTP A patient with recurrent TTP due to high titers of ADAMTS13 inhibitors who used to have two relapses of TTP a year +ATG +CHP +CHP +ATG +CHP +ATG +ATG 700 600 +CyA Vin Vin Vin Vin +Vin +Vin Vin +Vin +Vin +Ig +Ig +Ig 500 Vin ATG 400 ## 300 +FFP 200 100 0 0 10 20 30 40 50 60 70 80 90 100 110 120 months : Plasma exchange; Vin: vincristine; ATG: antiplatelet agents; CyA: cyclosporin A; CHP: cyclophosphamide; #: plasma exchange, vincristine, antiplatelet agents and corticosteroids; Ig: immunoglobulins; FFP: fresh frozen plasma; : corticosteroids; : splenectomy; : transient ischemic attack; : ADAMTS13 activity <6%, anti-ADAMTS13 inhibitors present. Galbusera et al., Blood 2005
  22. 22. PROPHYLAXIS WITH RITUXIMAB IN RECURRENT TTP - Rituximab caused progressive disappearance of inhibitors and increase of protease activity that lasted 14 months - A second course of rituximab induced a prompt recovery of ADAMTS13 activity and disappearance of inhibitor - Plasmapheresis had a small transient effect on ADAMTS13 activity and on inhibitor titer ADAMTS-13 activity (%) 35 18 Inhibitor titer (BU) 30 15 25 12 9 20 13 6 15 3 10 0 6 -25 -20 -15 -10 -5 0 0 100 200 300 400 500 600 700 800 days 3 courses of plasmapheresis 4 rituximab doses : anti ADAMTS13 IgG titer: 1:1600 : anti ADAMTS13 IgG titer: negative Galbusera et al., Blood 2005
  23. 23. PROPHYLAXIS WITH RITUXIMAB IN RECURRENT TTP Patient Treatment FOLLOW-UP no no Day 0 3 mo 6 mo 12 mo 18 mo 24 mo 30 mo 40 mo 03 1 ADAMTS13# -activity <6 15 21 14 <6 32 10 <6 -inhibitors 2.3 Neg Neg Neg 6.5 Neg Neg 4.4 Prophylactic Relapse CD20% 9 1 3 6 retreatment 1 4 10 mo later 04 1 ADAMTS13# -activity <6 55 74 91 70 84 56 45 -inhibitors 1.9 Neg Neg Neg Neg Neg Neg Neg CD20% 7 0 0.2 3 3.2 7.5 nd nd 05 1 ADAMTS13# -activity <6 59 64 50 24 23 <6 25 -inhibitors 3.4 Neg Neg Neg Neg Neg Pos Neg Prophylactic CD20% nd 1 1 nd nd nd retreatment 4.1 1 infusion # ADAMTS13 activity is expressed as % (normal range: 50-150%) Inhibitors are expressed as Bethesda units Data from the International Registry of Familial and Recurrent HUS/TTP
  24. 24. TTP PATIENT TREATED WITH RITUXIMAB BOTH IN ACUTE AND REMISSION PHASES FOLLOW-UP Patient Treatment no no Day 0 2 mo 3 mo 6 mo 9 mo 12 mo ADAMTS13# 06 1 -activity <6 33 56 46 <6 acute -inhibitors + Neg Neg Neg 3.6 Prophylactic treatment ADAMTS13# -activity <6 75 78 <6 <6 06 2 -inhibitors 3.6 Neg Neg +/- 2.5 remission Mild disease relapse ADAMTS13# 3 06 -activity <6 60 53 16 acute -inhibitors 2.5 Neg Neg Neg # ADAMTS13 activity is expressed as % (normal range: 50-150%) Inhibitors are expressed as Bethesda units Data from the International Registry of Familial and Recurrent HUS/TTP
  25. 25. CONCLUSIONS Our observations confirmed that Rituximab as adjunctive therapy in patients with TTP not responding to conventional therapies induced remission • Rituximab can be used as preventive therapy in patients at high risk of relapses • ADAMTS13 activity and inhibitors should be monitored during follow-up • Trials are needed to evalute: - parameters that should be used to predict relapse and indicate retreatment - response rate and long term side effects
  26. 26. RITUXIMAB FOR TREATMENT OF aHUS WITH ANTI-CFH ANTIBODIES In a 10-year-old girl with high levels of anti-CFH autoantibodies, plasma exchange combined with prednisone and azathioprine only transiently decreased the antibody titer. Rituximab (375 mg/m2/week x 4 weeks) led to a complete B cell depletion and maintained anti-CFH antibody at low levels during the following 4 months. Kwon et al, Nephrol Dial Transplant , 2008 In a 7 year old boy, combined treatment with FFP and Rituximab resulted in reduction in CFH autoantibody levels and induced clinical remission. Wigger et al, Pediatric Nephrol 2008
  27. 27. Laboratory Clinical Marina Noris Giuseppe Remuzzi Roberta Donadelli Piero Ruggenenti Chiara Mossali Erica Daina Chiara Fenili Elena Bresin Annalisa Sorosina Sara Gamba Jessica Caprioli Collaborations Rossella Piras Caterina Mele Peter Zipfel Erica Rurali Matthew Pickering Veronique Fremeaux-Bacchi Grants Tim Goodship John Atkinson Santiago Rodriguez DeCordoba

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